[Long-term efficacy and safety of divozilimab during 2-year treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-4/MIRANTIBUS]. / Effektivnost' i bezopasnost' dvukhletnei terapii divozilimabom u patsientov s rasseyannym sklerozom v ramkakh randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya BCD-132-4/MIRANTIBUS.

OBJECTIVE: To evaluate the efficacy and safety of the anti-CD20 monoclonal antibody divozilimab (DIV) used as an intravenous infusion at a dose of 500 mg every 24 weeks during 100 weeks for the treatment of patients with multiple sclerosis (MS), including relapsing-remitting multiple sclerosis (RRMS) and secondary progressive MS (SPMS) with relapses. MATERIAL AND METHODS: The multicenter, randomized, double-blind and double-masked phase III clinical trial (CT) BCD-132-4/MIRANTIBUS (NCT05385744) included 338 adult patients with MS distributed in a 1:1 ratio into two groups: DIV 500 mg and teriflunomide (TRF) 14 mg. After screening, subjects were included in the main CT period, which consisted of two cycles of therapy over 48 weeks, then entered an additional period from weeks 49 to 100, which included three cycles of therapy. The efficacy was assessed based on the results of brain MRI and registration of data on relapses. RESULTS: 308 subjects completed 5 therapy cycles according to the study protocol. An analysis of the effectiveness of DIV therapy over 2 years showed a persistent suppression of MRI and clinical activity of the disease in comparison with TRF, which was confirmed by all the studied MRI indicators (including CUA; total number of gadolinium-enhancing (GdE) lesions on T1-weighted scans ; number of new or enlarged lesions on T2-weighted scans; lesions volume change on T2-weighted scans; change in the volume of hypointense lesions on T1-weighted scans). The use of DIV was associated with a statistically significant decrease in ARR compared to TRF (p=0.0001). The ARR in the DIV group was 0.057, in the TRF group - 0.164 with 95% confidential interval for the frequency ratio [0.202; 0.593]. The incidence of GdE lesions on T1-weighted scans in the DIV group was significantly lower than in the TRF group. The average number of such lesions was 0.0±0.08 and 1.0±4.46 in the DIV and TRF groups, respectively (p<0.0001). Progression of EDSS was detected in 18 (10.7%) and 36 (21.3%) patients in the DIV and TRF groups, respectively (p=0.0075). The proportion of patients with relapses was 11.2% (n=19) in the DIV group and 23.1% (n=39) in the TRF group (p=0.0039). In the subpopulation of patients with SPMS, no cases of increase in EDSS were detected, and not a single case of exacerbation was recorded over 2 years of using DIV. Also, DIV has shown a favorable safety profile. Among the adverse reactions (AR), infusion reactions and laboratory abnormalities, such as a decrease in the number of leukocytes, neutrophils, and lymphocytes, were most often recorded. Identified AR were expected, had mild to moderate severity, and resolved without any negative consequences. CONCLUSION: The results of the BCD-132-4/MIRANTIBUS CT indicate a high sustained efficacy and safety of long-term use of DIV in comparison with TRF during 2 years of therapy.

[Tremor-dominant form of Parkinson's disease]. / Tremor-dominantnaya forma bolezni Parkinsona.

The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic rest tremor, patients with PD may experience tremor of other modalities: postural tremor, kinetic tremor, which reflects a multimodal mechanism of tremor formation involving multiple neurotransmitter systems. The unpredictable response to therapeutic options, the ambiguous response to levodopa, also reflects the role of multiple underlying pathophysiological processes. Among the drug methods of tremor correction, preference is given to dopamine receptor agonists - due to the spectrum of their pharmaceutical action, high efficiency in relation to all leading motor and a number of non-motor manifestations. The evidence for advanced neurosurgical, non-invasive modalities is mixed, and there are insufficient comparative studies to assess their efficacy in patients with tremor-dominant forms of PD.

[Postural stability and walking in Parkinson's disease]. / Postural'naya ustoichivost' i khod'ba pri bolezni Parkinsona.

The article is of an overview nature and is devoted to movement disorders in Parkinson's disease. The article discusses the existing problems according to the latest literature data, a review on the treatment and rehabilitation of postural instability. Special attention in the article is paid to dopamine receptor agonists - namely, piribedil, prescribed for the correction of these disorders.

[Efficacy and safety of antiCD20 monoclonal antibody divozilimab during 48-week treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-4/MIRANTIBUS]. / Effektivnost' i bezopasnost' 48 nedel'nogo primeneniya monoklonal'nogo antitela protiv CD20 divozilimaba u patsientov s rasseyannym sklerozom: rezul'taty randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya BCD-132-4/MIRANTIBUS.

OBJECTIVE: To evaluate the efficacy and safety of the anti-CD20 monoclonal antibody divozilimab (DIV) used as an intravenous infusion at a dose of 500 mg for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) in comparison with the teriflunomide (TRF). The study of the efficacy and safety of the use of the drug DIV was carried out for 48 weeks of therapy. MATERIAL AND METHODS: The multicenter, randomized, double-blind and double-masked phase III clinical trial (CT) BCD-132-4/MIRANTIBUS included 338 adult patients with RRMS distributed in a 1:1 ratio into two groups: DIV 500 mg and TRF 14 mg. After screening, subjects were included in the main CT period, which consisted of two cycles of therapy over 48 weeks. The primary end point was «Mean annualized relapse rate 48 weeks after the last patient is randomized in the study¼. RESULTS: 321 subjects completed 48 weeks of therapy according to the study protocol. The analysis of the of efficacy data for the primary endpoint successively proved the hypothesis of superiority of the test drug DIV at a dose of 500 mg over the reference drug TRF. A rapid suppression of acute disease activity according to the brain MRI and clinical manifestations of the disease was shown after the first infusion of DIV in patients with RRMS. Thus, after 48 weeks of therapy in patients treated with DIV, there were no T1 gadolinium-enhancing lesions, while in the TRF group such lesions were observed in 20.7% (35/169) of subjects. Evaluation of the CUA per scan showed that the mean values for the estimated period were statistically significantly lower in the DIV drug group compared to the TRF group: the ratio of the adjusted per scan rates (DIV/TRF) was 0.125 [95% CI: 0.089; 0.177]. Over the 48 weeks of therapy, the proportion of subjects with relapses was 9.5% (n=16/169) in the DIV group and 19.5% (33/169) in the TRF group (p=0.0086). DIV has shown a favorable safety profile. Among the adverse reactions (AR), infusion reactions and deviations of laboratory data, such as a decrease in the number of leukocytes, neutrophils, and lymphocytes, were most often recorded. Identified AR were expected, had mild to moderate severity, and resolved without any negative consequences. CONCLUSION: The results of the clinical study indicate the high efficacy and safety of DIV in comparison with TRF.

[Analysis of GBA mutations in patients with Parkinson's disease in the Krasnoyarsk region]. / Analiz mutatsii v gene GBA u patsientov s bolezn'yu Parkinsona Krasnoyarskogo regiona.

OBJECTIVE: To analyze mutations and polymorphisms in exons 2, 7, 8, 9, 10 and 11 of the glucocerebrosidase (GBA) gene in patients of the Krasnoyarsk region diagnosed with Parkinson's disease (PD). MATERIAL AND METHODS: Seventy-five patients with sporadic and familial forms of PD were examined. Genomic DNA was isolated from the whole blood of patients. The above mentioned exons of GBA were analyzed using Sanger sequencing. RESULTS: Various changes in the DNA structure of GBA were detected in 11 patients, thus, the overall frequency of variants was 14.7%, and the frequency of pathologically significant mutations (p.L444P, p.D409H, p.H255Q) was 5.3%. CONCLUSION: The frequencies of variants in GBA, one of the most common high-risk factors for PD, in patients of the Krasnoyarsk region turned out to be quite high and comparable to that in patients in other populations of the world. Thus, screening for GBA mutations is relevant for PD patients living in the Krasnoyarsk region as part of genetic counseling at present, and in the future it may be necessary for personalized treatment.

[Safety and efficacy of the Relatox in the treatment of patients with cervical dystonia (results of a multicenter simple blind comparative randomized study)]. / Bezopasnost' i effektivnost' preparata Relatoks v lechenii patsientov s tservikal'noi distoniei (rezul'taty mul'titsentrovogo prostogo slepogo sravnitel'nogo randomizirovannogo issledovaniya).

OBJECTIVE: The analysis of evaluation of the efficacy and safety of Relatox in patients with cervical dystonia (CD). MATERIAL AND METHODS: Russian multicenter simple comparative randomized clinical trial. The study involved 180 patients of both sexes aged 18-65 years from 3 research centers of the Russian Federation. All patients had previously established diagnosis of CD and were randomized to one of two groups at 1 visit after the inclusion procedure and signing of informed consent. Patients in group 1 (n=90) got injections of Relatox, in group 2 (n=90) - injections of Botox for the first time or no earlier than 4 months after the previous injection of Dysport 500 units, Botox 200 units or Xeomin 200 units. The assessment of changes in cervical dystonia followed, including of determination of changes in the severity of CD, assessed on the TWSTRS scale by the total score and by the defining values of the blocks, as well as on the scales: the Patient Global Impression of Improvement (PGI-I) and of adverse events (local and systemic reactions). Based on the form of cervical dystonia (torticollis, laterocollis, etc.), the drug was injected under electromyographic control into the target muscles: sternocleidomastoid, belt, trapezoidal, shoulder-lifting muscle. RESULTS: Equal efficacy, good tolerability and safety comparable to the comparison drug Botox was demonstrated in 12 weeks after injection of Relatox. The number of registered local and systemic reactions in both groups was insignificant and did not differ significantly (p>0.05). There were no significant differences in the results of laboratory parameters in patients of both groups (p>0.05). Serious adverse events were also not detected during the study. CONCLUSION: Obtained results indicate the safety, good tolerability and efficacy of Relatox in patients with CD comparable to Botox and can be recomemded for using by practitioners.

[Dynamics of cognitive impairments during L-dopa therapy in Parkinson's disease]. / Dinamika kognitivnykh narushenii u patsientov s bolezn'yu Parkinsona na fone L-DOFA terapii.

OBJECTIVE: To assess the dynamics of cognitive impairments (CI) in patients with Parkinson's disease (PD) during L-dopa therapy. MATERIAL AND METHODS: The randomized clinical study included 41 patients with a refined diagnosis of PD 2.5-3.5 stages by Hoehn-Yahr scale, mainly with akinetic-rigid and mixed forms, and with CI associated with PD. All patients were on levodopa therapy. The average duration of the disease was 5 years. The study participants were randomized into two groups according to the design. To assess the dynamics of CI, a neuropsychological study was carried out twice with an interval of 6 months: in group I - at the «peak and outcome¼ of L-DOPA therapy, and in group II - at the «outcome and peak¼ of levodopa therapy, respectively. Assessment of cognitive functions (CF) was carried out using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Scales for Outcomes in Parkinson's Disease-Cognition (SCOPA-Cog), Geriatric Depression Scale (GDS). RESULTS: The statistically significant improvement of CF at the «peak¼ of levodopa drugs and the deterioration at the «outcome¼ of L-DOPA therapy in the form of an increase in CI (p<0.05) was revealed. CONCLUSION: CI in PD, in a certain extent, may be dependent on L-DOPA therapy as well as motor manifestations. The most dependent on L-DOPA therapy CF were attention, speech, executive and visual-spatial functions.

[A novel approach to differential diagnosis of Parkinson's disease and essential tremor]. / Novyi podkhod v differentsial'noi diagnostike bol'nykh s bolezn'yu Parkinsona i essentsial'nym tremorom.

OBJECTIVE: To study tremor and olfactory dysfunction in patients with Parkinson's disease (PD), patients with essential tremor and healthy people for the differential diagnosis and to verify the hypothesis on the inverse dependence between tremor and olfactory dysfunction. MATERIAL AND METHODS: Olfactory dysfunction was studied in 45 patients with PD, 40 patients with essential tremor and 64 healthy controls. Tremor was studied in 90 people, including 30 controls and 30 patients with PD and essential tremor. The olfactory function was tested with Sniffin' Sticks test. Tremor parameters were studied with wireless monitoring instrument for electrophysiological signals record, where three essential data flows have been recorded: electromyogram, gyroscope and acceleration. The instrument recorded the frequency and amplitude of each parameter. The data were analyzed with IBM SPSS Statistica 2.3 software using standard methods. Besides, non-linear statistics using ViDaExpert software with elastic map technique was utilized. RESULTS AND CONCLUSION: The elastic map perfectly separated the patients with PD and essential tremor, as well as healthy controls. Three clusters were observed. The analysis of composition of the clusters proved the better quality of olfactory function of the patients with essential tremor compared to the patients with PD. This bias confirms the hypothesis on the inverse dependence between the tremor level and olfactory dysfunction.

[Possibilities of non-drug treatment for Parkinson's disease]. / Vozmozhnosti nemedikamentoznykh metodov lecheniya patsientov s bolezn'yu Parkinsona.

In this article, non-drug methods of treatment of Parkinson's disease are reviewed. Particular attention is given to the motor symptoms of disease, specifically to gait disorders. Information about objective methods of gait impairment is presented. Own results that confirm the effect of a method of tempo-rhythmical correction of walk in patients with Parkinson's disease (PD) and vascular parkinsonism as well as a device for assessment of gait parameters developed by the authors are analyzed. The efficacy of other methods of gait correction using external cues, study design and level of evidence are analyzed as well. Information about possibilities of physical therapy and ergotherapy for correction of different symptoms of Parkinson's disease is presented. Positive and negative results of transcranial magnetic stimulation, light therapy and transcranial micropolarization in PD are analyzed. Basis non-drug methods of PD treatment, which currently have insufficient level of evidence (methods of mental relaxation and auditory training, methods of whole body vibration (vibromassage), laser therapy (photoacoustic therapy), acupuncture), are described in brief. Perspectives of the method of gait recovery in PD using tempo-rhythmic correction are emphasized.

[The study of the efficacy of Botulinum toxin type A in patients with poststroke upper-limb spasticity ULIS-II: an analysis of Russian patients].

AIM: To assess the efficacy of Botulinum toxin type A (BoNT-A) injections in routine practice. MATERIAL AND METHODS: An international, post-marketing, multi-center, observational, prospective, longitudinal study included patients ≥18 years with poststroke upper-limb spasticity in whom a decision to inject BoNT-A had already been made, and who had no previous treatment with BoNT-A or BoNT-B within the last 12 weeks. The responder rate was assessed by the patient-centered goal attainment scaling (GAS). RESULTS AND CONCLUSION: The study included 7 Russian research centers (41 patients). Sixteen patients (39%) received BoNT-A injections prior to entering the study. During the treatment, 29 patients (70.7%) received dysport injections; 2 (4.9%) botox injections, 8 (19.5%) xeomin injections and 2 (4.9%) other BoNT-A agents. The primary treatment goals were successfully attained in 87.8%, secondary treatment goals in 88.3%. An improvement in passive function as primary goal and as secondary goal were achieved in 100%, in the range of movement in 94.9%, pain reduction in 82.4%, improvement in active function of the upper limb in 76.5%, reduction in involuntary movements (associated reactions) in 83.3% of cases. Investigators' global assessment of benefits revealed that 97.6% of patients showed positive effects from BoNT-A injections. Pateitnts' assessment of global benefits was slightly lower - 90,2% of patients reported positive treatment effects When assessed by patients, the rate of global benefits was 90.2%. Botulinum-toxin therapy is an effective treatment option. In the vast majority of patients, it allows both for reduction in muscle tone and functional benefits that could improve quality of life of the patients.

[Tempo-rhythmic correction of gait in Parkinson's disease].

OBJECTIVE: To evaluate the effectiveness of the method of tempo-rhythmic correction (TRC) of gait on slowing of the disease progression in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Authors have used the device to determine step-speed performance parameters, method TRC of gait, a quality of life questionnaire (PDQ-39). RESULTS: The method of TRC improved gait and quality of life in patients with Parkinson's disease, reduced the pharmacoeconomic cost of treatment. CONCLUSION: A neuroprotective effect of the method of TRC may take place due to increasing the interval between PD stages, more recent emergence of new symptoms.

[Rehabilitation of disturbances of walking in parkinsonian patients].

Disturbances of walking is one of the most significant presentations of Parkinson's disease that frequently determine patient's status and quality of life. In Parkinson's disease (PD, which is the most frequent nosological form of parkinsonism (up to 80% of cases), disturbances of walking are related to dopaminergic mechanisms , e.g., hypokinesia and rigidity, and only partly respond to standard antiparkinsonian drugs. In less frequent vascular parkinsonism (VP), disturbances of walking develop early and do not respond to dopaminergic drugs. Therefore, the elaboration of non-pharmacological methods of treatment is urgent. Patients with PD and VP are characterized by shorter step length with the increase in the variability of length. The preliminary determination of the individual optimal frequency of sound waves provides the higher effectiveness of treatment. Audio stimulation using portable audio/sound reproduction devices is available in outpatient clinics and is able to maintain the achieved positive effect.

[Rehabilitation of gait disorders in patients with Parkinson's disease and vascular parkinsonism].

Thirty patients with Parkinson's disease (PD) and 30--with vascular parkinsonism (VP) have been studied. A soft-hardware-controlled complex "Dorozhka" elaborated previously by the authors was used to assess objectively the step length. The coefficient of step length variability (CSLV) which normal value is about 1 has been calculated. A method of tempo-rhythmic correction of gait including the synchronization of step with the rate of individually tailored exogenic sound stimulation has been applied. The dose of antiparkinsonian drugs was not changed during the rehabilitation. The decrease of mean step length and CSLV in patients with PD and VP was found. There were differential-diagnostic differences between individual gait profiles of PD and VP patients: patients with PD had the relatively even decrease of the length of all steps and in patients with VP the initiation of gait with the following increase of step length was affected. The significant increase of step length and CSLV (p<0.01), improvement on GABS and PDQ-39 scales were observed during and after the tempo-rhythmic correction of gait. The improvement of gait was correlated mostly with the increase of CSLV (two-fold in PD and 3-fold in VP). Therefore, the assessment of step variability allows to objectively differentiate the gait in patients with PD and VP and the method of tempo-rhythmic correction of gait with sound stimulation allows to improve significantly parameters of gait and patient's quality of life without changing the dose of antiparkinsonian drugs.

[Rehabilitation of gait using the method of tempo-rhythmic correction in patients with Parkinson's disease and vascular parkinsonism].

The authors have elaborated a method of tempo-rhythmic correction of gait based on synchronizing the step of patients with tempo of exogenic sound stimulation. This method has allowed to improve gait without increase of the levadopa dose that is important for prevention of complications caused by that medication. Taking into account a need of the objective estimation of walking for using this method and for solving diagnostic and expertise problems, an original soft-hardware-controlled complex "Dorozhka", which allows to analyze the length of each step and provides the dynamic observation of patients for choosing and estimation of medication and non-medication treatment, has been created. With a help of this complex, healthy controls of different age and patients with Parkinson's disease and vascular parkinsonism have been observed. Using step variability factor, statistically significant difference was found between the groups studied. The use of the soft-hardware-controlled complex "Dorozhka" confirmed efficiency of tempo-rhythmic correction of gait in rehabilitation of patients with Parkinson's disease and vascular parkinsonism.